The goal of this project is to evaluate the efficacy of modafinil as a detoxification and relapse-prevention agent for cocaine dependence. We hypothesize that modafinil will reverse cocaine-induced neuroadaptations affecting dopamine, glutamate, and GABA neurotransmitter systems. Because of its stimulant-like properties, modafinil is also likely to relieve severe cocaine withdrawal symptoms, which are associated with poor clinical outcome. In addition, recent controlled studies from our Center and another research group indicate that modafinil attenuates cocaine-induced euphoria. Modafinil has low abuse potential and its mechanism of action differs markedly from that of cocaine. We conducted a small (n=13), 8-week, open-label, outpatient study of modafinil in subjects with severe cocaine withdrawal symptoms, as measured by the Cocaine Selective Severity Assessment (CSSA). Modafinil-treated subjects had superior rates of cocaine-free urine toxicology (48%) and treatment retention (74%), which compared favorably to cocaine-free urine toxicology (6.5%) and treatment retention (43%) rates in a group (n=23) of placebotreated, high CSSA subjects from another clinical trial conducted concurrently in our clinic. Also, several subjects indicated that modafinil eliminated or reduced their ability to experience euphoria after using cocaine. The proposed project will recruit cocaine-dependent subjects who will be randomized into one of three arms and treated double-blind for 8 weeks with either modafinil (200 mg/day, n=70), modafinil (400 mg/day, n=70), or placebo (n=90). We will use Urn randomization to stratify subjects across the experimental conditions on three baseline variables: high baseline CSSA scores (equal to or >22), gender, and positive cocaine toxicology at screening. Subjects will receive twice-weekly cognitive behavioral therapy (CBT) and 3 research assessments per week, including urine testing and questionnaires measuring craving, cocaine withdrawal, cocaine use, and medication side effects. Follow-up visits will be scheduled 3 and 6 months after randomization. Our primary aim is to determine whether modafinil improves cocaine abstinence (as measured by urine testing) and treatment retention. The secondary aims are to determine the effects of modafinil on secondary outcomes, the moderating effects of CSSA scores on response to modafinil, and the duration of potential modafinil effects.